The prognosis of patients with malignant gliomas remains dismal. To treat patients with this deadly disease more effectively, we must identify the common aberrations in the signaling pathways that are responsible for the invasive and drug-resistant nature of malignant gliomas. Merlin is a member of the Band 4.1 superfamily proteins. Mutations and deletions of merlin cause the neurofibromatosis type 2 (NF2), which is characterized by development of schwannomas, meningiomas, and ependymomas. Mutations of the NF2 gene have also been found in other cancers, suggesting that merlin is important for a variety of cancers. We have demonstrated recently that merlin is absent or down regulated in high-grade gliomas and that increased expression of merlin dramatically inhibits subcutaneous and intracranial growth of human gliomas in vivo. In addition, we demonstrated that increased expression of merlin is linked to activation the Lats2 tumor suppressorsignaling pathway and inhibition of Wnt and c-Met oncogenic signaling pathways. We showed that Lats2, canonical Wnt, RhoA, and c-Met signaling pathways play important roles in glioma growth in vivo. Based on these results, we hypothesize that merlin is a key negative regulator of the growth and progression of human gliomas and that the essential downstream signaling pathways of merlin are the Lats2, Wnt, and c-Met signaling pathways in human glioma cells. We further hypothesize that merlin can sensitize the response of glioma cells to the chemotherapeutic drugs in vivo. Two specific aims are proposed to test these hypotheses. Aim 1 is to determine the essential downstream effectors of merlin in malignant human gliomas by establishing that merlin activates Lats2 signaling and inhibits Wnt and c-Met signaling pathways. Aim 2 is to provide a novel therapeutic strategy for human gliomas by establishing that merlin sensitizes the response of glioma cells to chemotherapeutic drugs in vivo. Results from the proposed studies will advance our understanding in the essential role of merlin signaling in glioma progression and will establish that the essential downstream signaling pathways of merlin are prime targets for anti-glioma therapy and provide strong basis to conduct future preclinical studies to test the existing pharmacological agents that inhibit these essential downstream signaling pathways of merlin. Therefore, this proposal has high biological and clinical relevance